- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01282385
Hemodynamic Effect of Simvastatin With Beta Blockers in Clinical Portal Hypertension (SIMBETA)
Hemodynamic Effect of the Combination of Simvastatin With Non-cardioselective Beta Blockers in Patients With Cirrhosis and Clinically Significant Portal Hypertension
In the genesis and maintenance of PH associated with liver cirrhosis are two mechanisms that act synergistically. The first is an increase in hepatic vascular resistance, due in part to the disruption of liver structure inherent cirrhosis, and increased hepatic vascular tone is caused by the contraction of perivascular smooth muscle cells, myofibroblasts and hepatic stellate cells, which represents about 30% of global intrahepatic resistance and is believed to be due to the production Defective nitric oxide (NO). The second mechanism, which maintains and exacerbates HTP, is an increase of splanchnic blood flow caused by increased NO and other vasodilators at this level
In this regard, we believe that in patients with compensated liver cirrhosis, with portal pressure gradient> 10 mmHg, both acute responders betablockers test as non-responders, the association of antifibrotic drugs and / or vasodilators, chronic liver selective May be beneficial in the control of portal hypertension
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This study was prospective, randomized, controlled, double blind, in which patients who met the inclusion criteria and give written consent to participate in the study underwent a baseline hemodynamic study to determine the portal pressure gradient (GPSH). During the event, will assess the acute response to intravenous administration of propranolol. It is considered good hemodynamic response to declining GPSH >20% from baseline or decrease to <12 mmHg. At the conclusion of the baseline hemodynamic study patients will be divided into 2 treatment groups:
a) patients responding to treatment with beta-blockers, in which she was treated with nadolol at doses of 40mg/24horas (increasing the dose every 2-3 days as tolerated, to a maximum of 240 mg / 24 hours. Subsequently randomized into two treatment arms, double-blind:
a.1: simvastatin 20 mg capsules, starting at doses of 20 mg / 24 hours, may increase to 40 mg according to clinical and laboratory tolerance.
a.2: placebo capsules with external characteristics similar to simvastatin.
b) non-responders to treatment with beta blockers, carvedilol receive treatment with an initial dose of 6.25 mg / 24 hours, may increase to 25mg/dia if good clinical tolerance (HR and BP monitoring) and analytical (renal function and electrolyte disturbances) . Subsequently randomized into two treatment arms, double-blind b.1: simvastatin 20 mg capsules, starting at doses of 20 mg / 24 hours, may increase to 40 mg according to clinical and laboratory tolerance.
b.2: placebo capsules with external characteristics similar to simvastatin.
In order to evaluate the long-term hemodynamic effect, patients will receive treatment for a month and hemodynamic study will be repeated to completion.
Study Type
Enrollment (Anticipated)
Phase
- Phase 4
Contacts and Locations
Study Contact
- Name: Candido Villanueva, PHD
- Phone Number: 0034 5565917
- Email: cvillanueva@santpau.cat
Study Contact Backup
- Name: Angela Puente, MD
- Phone Number: 00345565917
- Email: apuentesa@santpau.cat
Study Locations
-
-
-
Barcelona, Spain, 08025
- Hospital de la Santa Creu i Sant Pau
-
Principal Investigator:
- Candido Villanueva, mPHD
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Sub-Investigator:
- Angela Puente, PHD
-
Contact:
- Candido Villanueva, mPHD
- Phone Number: 0034935565917
- Email: cvillanueva@santpau.cat
-
Contact:
- Angela Puente, PHD
- Phone Number: 0034935565917
- Email: apuentesa@santpau.cat
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Liver cirrhosis diagnosed by previous biopsy or by clinical, laboratory, ultrasound,
- PPG> 10 mmHg,
- Presence of large esophageal varices or small varices with red spots, varices of any size and Pugh C, and / or gastric fundic varices of any size, in a recent gastroscopy (<1 month)
- Absence of previous episodes of gastrointestinal bleeding
- Written informed consent.
Exclusion Criteria:
- Age <18 and> 80 years;
- Episode of variceal bleeding,
- Thrombosis splenoportal axis,
- Hepatocarcinoma,
- Terminal liver failure (Child-Pugh scale> 13 points);
- Any comorbidity involving a medical drugs and / or a life expectancy <12 months,
- Severe chronic renal insufficiency (creatinine> 150 g / L),
- Absolute contraindication or allergy treatment with statins to simvastatin;
- Concomitant potent inhibitors of CYP3A4 (eg., itraconazole, ketoconazole, inhibitors of HIV protease, erythromycin, clarithromycin, telithromycin and nefazodone),
- Pretreatment (<1 month) or other lipid-lowering with simvastatin,
- Previous episodes rhabdomyolysis;
- Contraindication to beta-blockers (COPD with bronchial hyperresponsiveness, aortic stenosis, AV block, intermittent claudication, severe psychosis, bronchial asthma),
- Hypersensitivity to beta blockers,
- Concomitant administration of potent inhibitors of cytochrome P-450 (quinidine, fluoxetine, paroxetine, and propafenone)
- Active alcoholic hepatitis,
- Refusal to participate in the study or the informed consent claim;
- Pre-treatment with beta blockers or nitrates, or endoscopic treatment for varicose veins or portosystemic shunts;
- Pregnancy and lactation.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: placebo
|
placebo capsules with external characteristics similar to simvastatin administrated each 24 hours.
|
Experimental: simvasatin
a) patients responding to treatment with beta-blockers, in which she was treated with nadolol Subsequently randomized into two treatment arms, double-blind: a.1: simvastatin 20 mg capsules, starting at doses of 20 mg / 24 hours, may increase to 40 mg according to clinical and laboratory tolerance. a.2: placebo capsules with external characteristics similar to simvastatin. b) non-responders to treatment with beta blockers, receive treatment with carvedilol.Subsequently randomized into two treatment arms, double-blind b.1: simvastatin 20 mg capsules, starting at doses of 20 mg / 24 hours, may increase to 40 mg according to clinical and laboratory tolerance. b.2: placebo capsules with external characteristics similar to simvastatin. |
simvastatin 20 mg capsules, starting at doses of 20 mg / 24 hours, may increase to 40 mg according to clinical and laboratory tolerance
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
improvement of the hemodynamic response rate
Time Frame: 1 month.
|
The main objective is to assess whether, in patients with compensated cirrhosis, portal pressure greater than 10mmHg and esophageal varices at risk, the association of a liver selective vasodilator and simvastatin together with non-cardioselective beta blockers can improve the hemodynamic response rate.
|
1 month.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Portal hypertension complications.
Time Frame: 1 month
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Development of complications related to portal hypertension (gastrointestinal bleeding related to portal hypertension, ascites, hepatic encephalopathy).
|
1 month
|
Adverse effects
Time Frame: 1 month
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adverse effects related to medication
|
1 month
|
Collaborators and Investigators
Publications and helpful links
General Publications
- Abraldes JG, Albillos A, Banares R, Turnes J, Gonzalez R, Garcia-Pagan JC, Bosch J. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009 May;136(5):1651-8. doi: 10.1053/j.gastro.2009.01.043. Epub 2009 Jan 24.
- Bosch J. Carvedilol for portal hypertension in patients with cirrhosis. Hepatology. 2010 Jun;51(6):2214-8. doi: 10.1002/hep.23689. No abstract available.
- Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, Schepke M, Nevens F, Sauerbruch T, Heller J. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology. 2007 Jul;46(1):242-53. doi: 10.1002/hep.21673.
- Tripathi D, Therapondos G, Lui HF, Stanley AJ, Hayes PC. Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther. 2002 Mar;16(3):373-80. doi: 10.1046/j.1365-2036.2002.01190.x.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Liver Diseases
- Fibrosis
- Hypertension
- Liver Cirrhosis
- Hypertension, Portal
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Simvastatin
Other Study ID Numbers
- IIBSP-SIM-2010-04
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